Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/34—Tobacco-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention relates to oral film-like pharmaceutical formulations for the administration of deoxypeganine, its salts and derivatives, and to the use of these medicaments for the treatment of diseases or disease symptoms.
• Deoxypeganine (1, 2,3, 9-tetrahydropyrrolo [2, 1-b] quinazoline; total form form C 11 H 12 N) occurs in plants of the family Zygophyllaceae; Due to its pharmacological properties, deoxypeganine belongs to the group of reversible cholinesterase inhibitors. It also acts as a monoamine oxidase inhibitor. Deoxypeganine (other name: deoxyvasicin) is considered as a drug for therapeutic purposes, such as. B.
• Deso_ ⁇ ypeganin is preferably obtained by isolation from the steppe (Peganum harmala) or by chemical synthesis (e.g. SARGAZAKOV et al .; Khim. Prir. Soedin. 4 (1990), 506-507; MORRIS et al .; J Amer. Chem. Soc. 57 (1935), 951-954).
• Deoxypeganine is known to pharmaceutical science from the literature and in particular from patent documents.
• the use of conventional dosage forms, such as. B. tablets, capsules, suspensions or solutions, for the purpose of oral administration of deoxypeganine has the disadvantage that deoxypeganine is predominantly absorbed from the intestine, whereby it is subject to n- first-pass "metabolism.
• the dosage forms mentioned are not or only limited use in people who swallow pain or who refuse to swallow such medication.
• TTS transdermal therapeutic system
• the oral film-like pharmaceuticals according to the invention (also called “wafers”) surprisingly enable the transmucosal absorption of deoxypeganine (and its salts or derivatives) in the area of the oral mucosa.
• the film-shaped medicaments are preferably applied buccally or sublingually.
• the first-pass metabolism is largely prevented by means of the preparations according to the invention, and a rapid onset of action is made possible (within about 5 s to 10 min).
• the pharmaceuticals according to the invention are applied into the oral cavity, whereupon the active ingredient (s) are released from the film-like preparation due to the action of food fluid and are subsequently resorbed via the oral mucosa.
• the invention also includes muco-adhesive film-like preparations which are applied to the oral mucosa and at least temporarily adhere there.
• the active ingredient can also be applied directly over the mucous membrane area of the application site, where the film-like preparation is in direct contact with the oral mucosa.
• the invention also extends to dosage forms which are intended for application to other mucosal surfaces (e.g. rectally, vaginally or intranasally) of the human or animal body and which transmucosal administration of Enable deoxypeganine.
• the medicaments according to the invention can be administered in a simple, unobtrusive and safe manner, since, unlike tablets, no additional liquid is required for ingestion.
• film-like preparations of small thickness e.g. less than 0.1 mm are perceived as pleasant by the people to be treated.
• the medicaments according to the invention preferably contain the active substance deoxypeganine in the form of one of its water-soluble, pharmaceutically acceptable salts; Desoxypeganin- Hydrochloride and deoxypeganine hydrobromide are particularly preferred. However, deoxypeganine may also be in the free base form of the medicinal products.
• the invention further provides for the use of deoxypeganine derivatives, optionally in the form of pharmaceutically acceptable salts.
• Deoxypeganine and its salts can be prepared or isolated by one of the methods mentioned at the beginning, or can be purchased commercially.
• the medicaments according to the invention can optionally contain a combination of two or more of the aforementioned active substances or salts.
• the pharmaceuticals according to the invention additionally contain at least one further active ingredient, tailored to the respective indication.
• Active substances from the group of acetylcholines erase inhibitors, which include galanthamine, pyridostigmine, physostigmine, Neostig in, and the pharmaceutically acceptable salts of the aforementioned active substances are particularly suitable for this.
• the pharmaceuticals according to the invention can additionally contain at least one active ingredient which is not selected from the group of acetylcholinesterase inhibitors; for example, film-like preparations, that are used to treat nicotine abuse also contain opiate antagonists.
• the total active substance content of a film-like preparation according to the invention is preferably 0.5 to 40% by weight, preferably 5 to 30% by weight.
• the dose of active ingredient contained in a single preparation is preferably in the range from 1 to 500 mg, in particular 10 to 300 mg.
• the film-shaped medicaments preferably have at least one polymer-containing layer which serves as an active substance reservoir, which contains the active substance (s) and can release them under the action of saliva, the polymer content in this polymer-containing layer being 10 to 90%. , preferably 20 to 70 parts by weight S6, particularly preferably 20 to 60 parts by weight Ss.
• the preparation according to the invention consists of only a single layer containing the active substance.
• the invention also encompasses embodiments which provide a two-, three- or multi-layer structure, at least one layer containing active substance.
• the different layers can differ in terms of their active substance content (type, concentration), the mucoadhesive properties, the disintegration properties, the solubility, etc.
• “Film-like” means that, unlike conventional tablets, the medicaments according to the invention have a small thickness and are preferably flexible. Furthermore, they are generally able to adapt to the irregular surface contour of the oral mucosa after absorption of moisture.
• the total thickness of the active substance-containing films is preferably 0.05 to 3 mm, particularly preferably 0.1 to 1 mm, and in particular 0.1 to 0.5 mm.
• the individual drugs can have, for example, a round, oval, triangular to quadrangular or polygonal surface shape. Their surface area is preferably in the range from 0.5 to 20 cm 2 , in particular in the range from 1 to 10 cm 2 .
• Polymers which are suitable for the production of the polymer matrix mentioned above can in particular be selected from the following group: polyvinyl alcohols; Polyvinyl pyrrolidones; polyvinyl acetate; Polyethylene glycols; Polyethylene oxide polymers; polyurethane; Polyacrylic acid, polyacrylates, polymethacrylates; Poly (methyl vinyl ether maleic anhydride); Cellulose ethers, in particular ethyl cellulose, hydroxyethyl cellulose, propyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose; Cellulose acetate; Polysaccharides such as starch and starch derivatives; natural gums; Alginates, pectins, gelatin.
• the components mentioned can be used individually or in combination.
• the medicaments according to the invention can additionally contain one or more auxiliaries which are known to the person skilled in the art and can in particular be selected from the following groups: emulsifiers (for example polyethoxylated sorbitan fatty acid esters, polyethoxylated fatty alcohols, lecithin); Plasticizers (e.g. polyethylene glycol, glycerin and other polyalcohols, higher alcohols such as dodecanol, undecanol, octanol; sorbitol, mannitol and other sugar alcohols, dexpanthenol; triglycerides), fillers (e.g.
• emulsifiers for example polyethoxylated sorbitan fatty acid esters, polyethoxylated fatty alcohols, lecithin
• Plasticizers e.g. polyethylene glycol, glycerin and other polyalcohols, higher alcohols such as dodecanol, undecanol, o
• the weight fraction of these auxiliaries can be up to 60% by weight, in particular 5 to 40% by weight, in each case based on the entire preparation.
• the chemical or physical properties of the active ingredient-containing films can be influenced, such as, for. B. Swelling ability, diffusion properties, mucoadhesive properties, flexibility, disintegration ability.
• the film-shaped medicaments are mucoadhesive or have at least one mucoadhesive surface, which enables adherence to the oral mucosa during the application period.
• the mucoadhesive properties are essentially determined by the type of the polymer (s) forming the mucoadhesive layer and by the relative proportions of these polymers; in addition, these properties can be modified by the additives mentioned (e.g. fillers, plasticizers).
• the mucoadhesive layer preferably also contains an active ingredient.
• a mucoadhesive layer with a non-mucoadhasive layer.
• the presence of a non-mucoadhasive surface can prevent unwanted adherence to adjacent areas of the mucous membrane (e.g. tongue).
• Suitable polymers for the production of a mucoadhesive layer can be selected from the following groups: polyvinyl alcohols; Gelatin; Polyvinylpyrrolidone; polyacrylamide; polyacrylates; natural gums; Starch and starch derivatives, pullulan; Cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose), methyl cellulose, hydroxy ethyl cellulose and hydroxypropyl ethyl cellulose; and combinations of the aforementioned polymers.
• mucoadhasive properties can be modified by suitable auxiliaries known to the person skilled in the art.
• the film-shaped medicament is soluble in aqueous media, in particular in saliva.
• a quick release of active ingredient can be achieved.
• An embodiment is preferred in which the resolution takes place within 1 s to 5 min, particularly preferably within 3 to 30 s.
• the medicament can be formulated as a rapidly disintegrating dosage form which disintegrates rapidly in aqueous media, in particular in saliva, preferably within 1 s to 5 min, particularly preferably within 3 to 30 s.
• the solubility or disintegrability relates to the temperature conditions prevailing in the oral cavity (approx. 35 to 40 ° C).
• the film-shaped medicaments are characterized in that they contain the active substance (s) present in the oral cavity in such an amount within 30 minutes, preferably within 15 minutes, particularly preferably within 5 minutes release that an effective plasma level is reached.
• the film-like preparations are intended to enable a longer-lasting release of active ingredient, they are advantageously formulated as mucoadhesive, slowly soluble or slowly disintegrating films, which dissolve or disintegrate only after several hours (for example after 1 h, 6 h or 12 to 24 h).
• the invention also encompasses film-shaped drugs which are insoluble or non-disintegrable in aqueous media under the conditions mentioned; in the- In this case, the active ingredient is released exclusively by diffusion of the active ingredient from the film into the environment. The active ingredient release is delayed, preferably over a period of up to 8 hours, in particular up to 24 hours.
• a depot effect can also be achieved if the active ingredient is encapsulated in particles (e.g. polymer particles), the shell of which slows down the diffusion.
• a film-like pharmaceutical form has at least one rapidly disintegrating or easily soluble layer and at least one slowly or non-disintegrating (or essentially insoluble), preferably mucoadhesive, layer, these two layers containing active ingredient. In this way, a quick initial dose can be combined with a maintenance dose of the active ingredient.
• the soluble or disintegrable medicaments mentioned can also be endowed with mucoadhasive properties. It is thereby achieved that such a preparation adheres to the application site in the oral cavity until it has dissolved or disintegrated.
• the solubility and the disintegrability are essentially determined by the type of the polymer (s) forming the respective layer (s) and by the relative proportions of these polymers; in addition, these properties can be modified by the additives mentioned (e.g. fillers, plasticizers).
• the soluble or disintegrable layer preferably also contains active substance.
• the film-shaped medicaments can be gelled or swellable in aqueous media, in particular in saliva. In this way a delay in drug release can be achieved.
• Polymers from the following group are particularly suitable for the production of water-soluble (or disintegrable) film-like preparations, or layers of such preparations: polyvinyl alcohols, polyvinylpyrrolidones, polyethylene oxide polymers, polyacrylamides, polyethylene glycol, polyvinyl acetate, polyacrylic acid, polyacrylates; Starch and starch derivatives, dextran; Cellulose derivatives (see above; in particular ethyl cellulose, propyl cellulose, carboxymethyl cellulose); Gelatin, and other gel-forming proteins; natural gums, pectins, alginates, pullulan, carrageenan, xanthan, tragacanth, chitosan, agar-agar, agarose.
• the substances mentioned can be used individually or in various combinations, also in combination with auxiliaries. They can also be used to produce the above-mentioned gellable or swellable films or layers, optionally using auxiliaries.
• the film-like preparations according to the invention are present as solidified foams.
• the production of such foams has been described, for example, in DE-A-100 32 456.
• the film-like medicaments according to the invention can be obtained, for example, by the following method:
• a first layer for example, is first produced and dried as described above.
• the coating composition for the second layer is applied to the dried layer and dried.
• the film-shaped medicaments according to the invention can advantageously be used for the treatment of diseases or disease symptoms which are caused by a deficiency in acetylcholine or in which such a deficiency occurs. They are also suitable for the treatment of diseases in which a deficiency of endogenous amines occurs and / or which can be influenced favorably by inhibiting monoamine oxides.
• the film-shaped medicaments are particularly suitable for the treatment of the diseases and symptoms mentioned at the outset, and for the prophylactic measures mentioned.
• the film-like preparations according to the invention can be used in particular for the medicinal therapy of the following diseases and symptoms:
• Alzheimer's disease especially Alzheimer's dementia
• Depression especially Alzheimer's dementia
• Chronic fatigue syndrome sleep disorders
• Schizophrenia Mania
• Parkinson Central nervous system disorders, in particular memory disorders caused by exposure to psychotropic substances, in particular intoxications with such substances
• Poisoning from nerve agents or warfare agents in particular organophosphorus substances
• Alcoholism or addiction to nicotine misuse of other chemical substances
• the film-like preparation is introduced into the oral cavity (buccal, sublingual) and, in the case of mucoadhasive films, adhered to the buccal mucosa.
• Other areas of the oral mucosa e.g. palate, sublingual, gingival
• the application is repeated as often as necessary, for example at intervals of preferably 1 to 6 hours.
• the daily dose of deoxypeganine is generally in the range from 50 to 750 mg.
• a film-like preparation according to the invention can be obtained, for example, with the following formulation.
• the components are dissolved in water with heating and the solution obtained is coated on a smooth, inert base (polished steel strip). After drying (approx. 25-80 ° C) a mucoadhesive film is obtained, which can be detached from the base and divided into unit areas of 5 cm 2 at a time by punching. example

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• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Psychiatry (AREA)
• Epidemiology (AREA)
• Addiction (AREA)
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• Physiology (AREA)
• Toxicology (AREA)
• Hospice & Palliative Care (AREA)
• Anesthesiology (AREA)
• Pain & Pain Management (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2003
  • 2003-11-24 DE DE10354894A patent/DE10354894A1/de not_active Withdrawn
• 2004
  • 2004-11-08 US US10/580,485 patent/US20070155774A1/en not_active Abandoned
  • 2004-11-08 JP JP2006540236A patent/JP2007512270A/ja active Pending
  • 2004-11-08 CA CA002546950A patent/CA2546950A1/en not_active Abandoned
  • 2004-11-08 WO PCT/EP2004/012606 patent/WO2005053698A1/de active Application Filing
  • 2004-11-08 MX MXPA06005733A patent/MXPA06005733A/es active IP Right Grant
  • 2004-11-08 UA UAA200605675A patent/UA87291C2/ru unknown
  • 2004-11-08 EP EP04797702A patent/EP1827402A1/de not_active Withdrawn
  • 2004-11-08 CN CNA2004800347435A patent/CN1886137A/zh active Pending
  • 2004-11-08 EA EA200601015A patent/EA008945B1/ru not_active IP Right Cessation
  • 2004-11-08 BR BRPI0416415-6A patent/BRPI0416415A/pt not_active IP Right Cessation
  • 2004-11-08 AU AU2004294690A patent/AU2004294690B2/en not_active Ceased
  • 2004-11-08 NZ NZ547282A patent/NZ547282A/en unknown
  • 2004-11-08 KR KR1020067010114A patent/KR20060123194A/ko not_active Application Discontinuation
  • 2004-11-17 TW TW093135211A patent/TW200526223A/zh unknown
  • 2004-11-23 MY MYPI20044848A patent/MY141008A/en unknown
  • 2004-11-24 AR ARP040104345A patent/AR046665A1/es unknown
• 2006
  • 2006-05-05 ZA ZA200603542A patent/ZA200603542B/xx unknown
  • 2006-05-18 IL IL175746A patent/IL175746A0/en unknown
  • 2006-06-09 NO NO20062668A patent/NO20062668L/no not_active Application Discontinuation

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